Caloric restriction (CR) has been known for many years to extend the maximum life span of a wide range of species. While a great deal of data has been gathered on the biological changes that accompany CR, the molecular basis of the life span extension is not understood. This largely stems from the lack of facile experimental models. One model that shows considerable promise is the budding yeast S. cerevisiae. Significant advances have been made in our understanding of how CR slows aging in this organism at the molecular level. Importantly, aspects of this pathway appear to be conserved in higher organisms. The major drawback of yeast as a model of aging is that life span is determined by micro-manipulating individual yeast cells. This has made it technically impossible to systematically screen for longevity mutants. To overcome this problem, we have devised the first plate assay for yeast life span, which we will use to screen for high-copy genes and mutations that extend life span. Genes that are relevant to CR will then be identified using color/growth assays for the level of rDNA silencing, a phenotype that is tightly linked to CR and longevity. NAD+ has emerged as a positively acting regulatory molecule that is required for CR-mediated life span extension. By boosting NAD+ levels to those normally found only in calorically restricted cells, we aim to essentially mimic CR and provide longevity even in the presence of ample calories. We will identify both genes and exogenous compounds that achieve this effect. The longer-term goal is to test the genes and compounds we identify for their ability to extend life span in C. elegans. The knowledge gained should serve to guide searches for compounds that retard aging in mammals.